Synthesis, spectrometric characterization and trypanocidal activity of some 1,3,4-thiadiazolines derivatives (original) (raw)
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African Journal of Pure and Applied Chemistry, 2011
The thiosemicarbazones of six aromatic ketones were synthesized as well as their 1,3,4-thiadiazolines derivatives obtained by cyclization under acetylating condition with yields going from 40 to 90%. The products purity was confirmed by mass spectrometry coupled with high-performance liquid chromatography (LC/MS) and there were characterized using spectrometry IR, NMR 1 H and 13 C (nuclear magnetic resonance). These compounds were then tested in vitro on Trypanosoma brucei brucei according to the "LILIT, Alamar Blue" method for a comparison of their trypanocidal activity. Thus, all thiosemicarbazones appeared much more active than their corresponding 1,3,4-thiadiazolines. Thiosemicarbazone 6a (IC 50 = 9.62 µM) was the most active of all thiosemicarbazones tested and it is the same for its thiadiazoline 6b (IC 50 = 49.03 µM) among 1,3,4-thiadiazolines.
Medicinal Chemistry Research, 2016
In this study, we synthesized a series of 1,3,4thiadiazole derivatives of R-(?)-limonene benzaldehydethiosemicarbazones (2a-k). We also determined the cytotoxicity in LLCMK 2 cells and the activity against epimastigote and trypomastigote forms of Trypanosoma cruzi, of these synthetic compounds and also of a series of 1,3,4thiadiazole without the monoterpene R-(?)-limonene (4ak). 1,3,4-Thiadiazole compounds showed significant trypanocidal activity and a high selectivity indexes. The vast majority of the monoterpene derivatives, substituted by R-(?)-limonene, presented better anti-T. cruzi activity than the non-substituted compounds. Regarding the cytotoxic profile, the compounds without the monoterpene R-(?)limonene were, in general, less toxic. The present findings indicate that the 1,3,4-thiadiazoles derivatives of R-limonene have potential trypanocidal activity that justify further studies to better understand the mechanism of action of these substances on T. cruzi.
New thiadiazine derivatives with activity against trypanosoma cruzi amastigotes
Folia Parasitologica, 2013
The cytotoxicity of 18 new 1,2,6-thiadiazin-3,5-dione 1,1-dioxides was evaluated. This group of products was previously assayed against epimastigotes of Trypanosoma cruzi and some of them showed a high antiprotozoal activity. Thereafter 13 compounds with a high anti-epimastigote activity and low cytotoxicity were selected to be assayed against amastigotes. Some of the products showed the same or even lower cytotoxicity than nifurtimox and benznidazole, but most of them were very toxic for macrophages at 100 µg/ml. Only one of the compounds had an anti-amastigote activity similar to that of reference drugs at 10 µg/ml, but unfortunately this disappeared at lower concentrations.
Medicinal Chemistry Research, 2012
To explore the structure-activity relationships of thiosemicarbazones on African trypanosome: Trypanosoma brucei brucei, a series of thirty-five thiosemicarbazones (1-35) have been synthesized and characterized by their 1 H NMR, 13 C NMR, and FT-IR spectra. All compounds were tested for trypanocidal activity using the method ''Lilit alamar blue''. The comparison of trypanocidal power of thiosemicarbazones was performed considering their structures. This study that was done using acetophenone thiosemicarbazone (1) as basic model, showed that: (a) the presence of lipophilic substituents in para position on benzene ring, (b) substitution of benzene ring and (c) substitution of hydrogen of thioamide function by a phenyl, strongly influence trypanocidal activity. The various modifications to basic structure (1) allowed the synthesis of 1-(4-chlorophenyl) ethylidene-4-phenyl-thiosemicarbazide (34). With a trypanocidal activity of 3.97 lM, this compound is the most active of the series.
Frontiers in Drug, Chemistry and Clinical Research, 2019
Chagas disease is a serious public health problem in Brazil and world. Caused by the protozoan Trypanosoma cruzi, it is estimated 6-7 million people infected worldwide. The only drug used to treatment is Benzonidazole, but this drug is only effective in the acute phase of the disease. This paper reports the synthesis and the anti-Trypanosoma cruzi activity of 4-thiazolidinone and 1,3-thiazole derivatives based in thiosemicarbazones previously described as potent trypanocidal agent, planned through the bioisosterism strategy. Therefore, the synthesis of 28 aryl-4-thiazolidinones (2a-r and 3a-j) was achieved, which aryl ring possesses halogens atoms in meta and para positions, and the heterocyclic system had lipophilic substituents. These compounds were thus evaluated as anti-T. cruzi agents against epimastigote, trypomastigote and amastigote forms of T. cruzi. Compounds were also tested its toxicity in L929 fibroblasts. In view to investigate a bioisosteric relationship between 1,3-thiazoles and 4-thiazolidinones, eighteen 1,3-thiazoles derived from trifluoromethyl thiosemicarbazone (4a-r) were also tested in the same model. It was possible to show that between the 46 tested compounds, those that possess a bromine (2a-r) atom showed better activity compared to compounds substituted by a trifluoromethyl group (3a-j) and to 1,3-thiazole derivatives (4a-r), which were inactive. In general, the 2a-r series showed low toxic profile in the cell line tested. Besides, compound 2h was the most active of then all when compared to the standard Benznidazole.
Memorias Do Instituto Oswaldo Cruz, 2002
Cytotoxicity assays of 24 new 3,5-disubstituted-tetrahydro-2H-1,3,5-thiadiazin-2-thione derivatives were performed. The 17 compounds with higher anti-epimastigote activity and lower cytotoxicity were, thereafter, screened against amastigote of Trypanosoma cruzi. Out of these 17 derivatives S-2d was selected to be assayed in vivo, because of its remarkable trypanocidal properties. To determine toxicity against J774 macrophages, a method based on quantification of cell damage, after 24 h, was used. Cell respiration, an indicator of cell viability, was assessed by the reduction of MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] to formazan. Antiamastigote activity was estimated after 48 h by microscopic counts of May Grünwald-Giemsa-stained monolayers. Nifurtimox and benznidazole were used as reference drugs. For the in vivo experiences, mice were infected with 10 4 blood trypomastigotes and then treated during 15 days with S-2d or nifurtimox by oral route. All of the compounds were highly toxic at 100 µg/ml for macrophages and a few of them maintained this cytotoxicity even at 10 µg/ml. Of the derivatives assayed against amastigotes 3k and S-2d showed an interesting activity, that was held even at 1µg/ ml. It is demonstrated that the high anti-epimastigote activity previously reported is mainly due to the non-specific toxicity of these compounds. In vivo assays assessed a reduction of parasitemia after administration of S-2d to infected mice.
Synthesis and trypanocidal activity of novel pyridinyl-1,3,4-thiadiazole derivatives
Biomedicine & Pharmacotherapy, 2020
Herein, we present the design, synthesis and trypanocidal evaluation of sixteen new 1,3,4-thiadiazole derivatives from N-aminobenzyl or N-arylhydrazone series. All derivatives were assayed against the trypomastigote form of Trypanosoma cruzi, showing IC 50 values ranging from 3 to 226 μM, and a better trypanocidal profile was demonstrated for the 1,3,4-thiadiazole-N-arylhydrazones (3a-g). In this series, the 2-pyridinyl fragment bound to the imine subunit of the hydrazine moiety presented pharmacophoric behavior for trypanocidal activity. Compounds 2a, 11a and 3e presented remarkable activity and excellent selectivity indexes. Compound 2a was also active against the intracellular amastigote form of T. cruzi. Moreover, its corresponding hydrochloride, compound 11a, showed the most promising profile, producing phenotypic changes similar to those caused by posaconazole, a well-known inhibitor of sterol biosynthesis. Thus, 1,3,4-thiadiazole derivative 11a could be considered a good prototype for the development of new drug candidates for Chagas disease therapy.
Evaluation of thiosemicarbazones and semicarbazones as potential agents anti-Trypanosoma cruzi
Experimental Parasitology, 2011
Synthetic thiosemicarbazones and semicarbazones were evaluated for their Trypanosoma cruzi trypomastigotes obtained from LLC-MK2 cell cultures. In general, thiosemicarbazone derivatives were most effective and among them the 4-N-(2 0 -methoxy styryl)-thiosemicarbazone was chosen, to compare the in vitro effect against amastigotes of T. cruzi lodged in mouse peritoneal and human macrophages. A potent trypanocidal effect was observed that was more pronounced against parasites internalized in human macrophages. A potential target for this compound was also evaluated by measuring the nitric oxide synthase activity through NADPH consumption. A significant decrease in enzyme activity was observed. In contrast to the cytotoxic effect observed with benznidazole, no macrophage toxicity was observed for any of the compounds, indicating that their activity was specific for the parasite forms investigated.
Bioorganic & Medicinal Chemistry, 2006
A novel series of thiosemicarbazone and aminoacyl-thiazolidones derivatives were synthesized. Their structure suggests that these compounds could have anti-Trypanosoma cruzi activity. Biological evaluation indicates that some of these compounds are able to inhibit the growth of T. cruzi in concentrations non-cytotoxic to mammalian cells. Docking studies were carried out in order to investigate the binding pattern of these compounds for the T. cruzi cruzain (TCC) protein, and these showed a significant correlation with experimental data.
Bioorganic & Medicinal Chemistry, 2015
Chagas disease is an infection caused by protozoan Trypanosoma cruzi, which affects approximately 8-10 million people worldwide. Benznidazole is the only drug approved for treatment during the acute and asymptomatic chronic phases of Chagas disease; however, it has poor efficacy during the symptomatic chronic phase. Therefore, the development of new pharmaceuticals is needed. Here, we employed the bioisosterism to modify a potent antiparasitic and cruzain-inhibitor aryl thiosemicarbazone (4) into 4-thiazolidinones (7-21). Compounds (7-21) were prepared by using a straightforward synthesis and enabled good to excellent yields. As a chemical elucidation tool, X-ray diffraction of compound (10) revealed the geometry and conformation of this class compounds. The screening against cruzain showed that 4-thiazolidinones were less active than thiosemicarbazone (4). However, the antiparasitic activity in Y strain trypomastigotes and host cell cytotoxicity in J774 macrophages revealed that compounds (10 and 18-21) are stronger and more selective antiparasitic agents than thiosemicarbazone (4). Specifically, compounds (18-20), which carry a phenyl at position N3 of heterocyclic ring, were the most active ones, suggesting that this is a structural determinant for activity. In infected macrophages, compounds (18-20) reduced intracellular amastigotes, whereas Benznidazole did not. In T. cruziinfected mice treated orally with 100 mg/kg of compound (20), a decreased of parasitemia was observed. In conclusion, we demonstrated that the conversation of thiosemicarbazones into 4-thiazolidinones retains pharmacological property while enhances selectivity.